Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome

Hirsch, Shira; Tam, Joseph

doi:10.3390/toxins11050275

Cited by 30 publications

(25 citation statements)

References 154 publications

(158 reference statements)

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“…Additionally, our observations also highlight the role of these lipids in growth/development and other phenotypes, which can be linked to metabolic status. As summarized, previous studies have already shown connections between nutrient status, metabolism and various components of the ECs in mammals [75][76][77]. It would thus be interesting to see if these newly identified EC-like molecules and FAs might play a crucial role in altering and modulating the metabolic status by interacting with key nutrient sensing and signaling pathways.…”

Section: Discussionmentioning

confidence: 86%

Juniperonic Acid Biosynthesis is Essential in Caenorhabditis elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids

Guha

Calarco

Gachet

et al. 2020

Cells

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In eukaryotes, the C20:4 polyunsaturated fatty acid arachidonic acid (AA) plays important roles as a phospholipid component, signaling molecule and precursor of the endocannabinoid-prostanoid axis. Accordingly, the absence of AA causes detrimental effects. Here, compensatory mechanisms involved in AA deficiency in Caenorhabditis elegans were investigated. We show that the ω-3 C20:4 polyunsaturated fatty acid juniperonic acid (JuA) is generated in the C. elegans fat-3(wa22) mutant, which lacks Δ6 desaturase activity and cannot generate AA and ω-3 AA. JuA partially rescued the loss of function of AA in growth and development. Additionally, we observed that supplementation of AA and ω-3 AA modulates lifespan of fat-3(wa22) mutants. We described a feasible biosynthetic pathway that leads to the generation of JuA from α-linoleic acid (ALA) via elongases ELO-1/2 and Δ5 desaturase which is rate-limiting. Employing liquid chromatography mass spectrometry (LC-MS/MS), we identified endocannabinoid-like ethanolamine and glycerol derivatives of JuA and ω-3 AA. Like classical endocannabinoids, these lipids exhibited binding interactions with NPR-32, a G protein coupled receptor (GPCR) shown to act as endocannabinoid receptor in C. elegans. Our study suggests that the eicosatetraenoic acids AA, ω-3 AA and JuA share similar biological functions. This biosynthetic plasticity of eicosatetraenoic acids observed in C. elegans uncovers a possible biological role of JuA and associated ω-3 endocannabinoids in Δ6 desaturase deficiencies, highlighting the importance of ALA.

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Section: Discussionmentioning

confidence: 86%

Juniperonic Acid Biosynthesis is Essential in Caenorhabditis elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids

Guha

Calarco

Gachet

et al. 2020

Cells

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“…As presented earlier, experimental data highlighted the therapeutic potential of CB1R blockade in renal fibrosis and CKD, regardless of the cause (metabolic or not) ( 12 , 13 , 15 – 18 , 45 ). Therefore, there is a growing interest for the industry to develop CB1R inhibitors with no BBB passage to improve tolerance compared with rimonabant ( 188 ).…”

Section: Cb1r Inhibition: a New Promising Therapeutic Target In Chronic Kidney Diseasesmentioning

confidence: 99%

Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox

Dao

François

2021

Front. Endocrinol.

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Chronic kidney disease (CKD) concerns millions of individuals worldwide, with few therapeutic strategies available to date. Recent evidence suggests that the endocannabinoid system (ECS) could be a new therapeutic target to prevent CKD. ECS combines receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R), and ligands. The most prominent receptor within the kidney is CB1R, its endogenous local ligands being anandamide and 2-arachidonoylglycerol. Therefore, the present review focuses on the therapeutic potential of CB1R and not CB2R. In the normal kidney, CB1R is expressed in many cell types, especially in the vasculature where it contributes to the regulation of renal hemodynamics. CB1R could also participate to water and sodium balance and to blood pressure regulation but its precise role remains to decipher. CB1R promotes renal fibrosis in both metabolic and non-metabolic nephropathies. In metabolic syndrome, obesity and diabetes, CB1R inhibition not only improves metabolic parameters, but also exerts a direct role in preventing renal fibrosis. In non-metabolic nephropathies, its inhibition reduces the development of renal fibrosis. There is a growing interest of the industry to develop new CB1R antagonists without central nervous side-effects. Experimental data on renal fibrosis are encouraging and some molecules are currently under early-stage clinical phases (phases I and IIa studies). In the present review, we will first describe the role of the endocannabinoid receptors, especially CB1R, in renal physiology. We will next explore the role of endocannabinoid receptors in both metabolic and non-metabolic CKD and renal fibrosis. Finally, we will discuss the therapeutic potential of CB1R inhibition using the new pharmacological approaches. Overall, the new pharmacological blockers of CB1R could provide an additional therapeutic toolbox in the management of CKD and renal fibrosis from both metabolic and non-metabolic origin.

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“…The signaling pathway and synthesis of endocannabinoid(s) are commonly dependent on externally stimulated factors such as metabolic dysregulation, cellular stress, and damage of tissue(s) [ 169 , 171 ]. Although ECS regulation is directed to change in response to obesity, the peripheral organs or the brain region of the body in response to obesity or after a high-fat diet stimulate the ECS [ 146 , 169 , 172 ]. A potential mechanism of the activation of the ECS may consist of an increased level of fatty acids in the diet.…”

Section: Autoimmune Disorders and Cannabinoidsmentioning

confidence: 99%

Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

et al. 2021

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In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

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Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome

Cited by 30 publications

References 154 publications

Juniperonic Acid Biosynthesis is Essential in Caenorhabditis elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids

Juniperonic Acid Biosynthesis is Essential in Caenorhabditis elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids

Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox

Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

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